13-alkyl-11beta-phenylgonanes

ABSTRACT

There are provided 13-alkyl-11beta-phenyl-gonanes of formula I ##STR1## wherein Z is an oxygen atom or N--OH; 
     R 2  is alpha- or beta-position methyl or ethyl; 
     R 1  is selected from heteroaryl radicals, cycloalkyl radicals, cycloalkenyl radicals, aryl radicals, alkenyl radicals, and alkyl radicals where R 2  is in the alpha-position and an ethyl radical where R 2  is in the beta-position; and 
     R 3  and R 4  are selected from one of two different groups of substituent pairs, the group from which the selection is made being determined by the position of R 2 .

This application is a division of application Ser. No. 07/374,809, filedJul. 3, 1989 now U.S. Pat. No. 5,273,971.

BACKGROUND OF THE INVENTION

This invention relates to novel gonanes and the like, processes forproducing same as well as starting materials, and methods of usingcompounds for their antigestagenic activity.

SUMMARY OF THE INVENTION

The present invention relates to 13-alkyl-11beta-phenyl-gonanes of thefollowing general Formula I ##STR2## in which Z stands for an oxygenatom or the hydroxyimino grouping N˜OH,

R¹ stands either for

a) a heteroaryl radical of Formula Ia ##STR3## and A═N, O or S and B-D-Emean the element sequence C-C-C, N-C-C or C-N-C or

b) a heteroaryl radical of Formula I b ##STR4## and A═N and B-D-E meanthe element sequence

C-C-C, N-C-C, C-N-C or C-C-N or

c) for a cycloalkyl, cycloalkenyl or aryl radical Ic or

d) for an alkenyl radical Id exhibiting straight-chain or branched, oneor more double bonds with 2 to 10 carbon atoms and optionally

the heteroaryl radical of Formula Ia is substituted by one or morehalogen radicals and/or one or more alkyl radicals with 1 to 3 carbonatoms

and the cycloalkyl, cycloalkenyl or aryl radical Id is substituted byone or more halogen, optionally protected hydroxy, alkoxy, oxidizedalkylthio and/or dialkylamino radicals optionally in the form of thesulfoxide or sulfone and/or of the N-oxide and

R² stands for an alpha- or beta-position methyl or ethyl radical, and ifR² is in alpha position,

R¹ stands additionally for a straight-chain or branched alkyl radicalwith 1 to 10 carbons atoms and R³ /R⁴ mean ##STR5## if R² is in betaposition

R¹ additionally stands for an ethyl radical, but R¹ cannot be thealkenyl radical isopropenyl and

R³ /R⁴ mean ##STR6## with R₅ in the meaning of a hydrogen atom or anacyl radical with 1 to 4 carbon atoms.

Y in the meaning of a hydrogen, chlorine, fluorine, iodine or bromineatom, an alkyl, hydroxyalkyl, alkoxyalkyl or acyloxyalkyl group eachwith 1 to 4 carbon atoms in the alkyl or acyl radical,

R₆ in the meaning of a hydrogen atom, a hydroxy group, an alkyl, O-alkylor O-acyl group each with 1 to 4 carbon atoms, o in the meaning of 0, 1,2 or 3,

R₇ in the meaning of a hydroxy or cyanide radical, an O-alkyl or O-acylgroup each with 1 to 4 carbon atoms and k in the meaning 0, 1 or 2,

Process for their production, pharmaceutical preparations containingthese compounds as well as the new starting materials and intermediateproducts and processes for their production,

Among the heteroaryl radicals possible according to Formula Ia, the3-thienyl, 3-furyl and 3-pyrrole radicals are preferred.

As heteroaryl radical of Formula Ib, according to the invention the3-pyridyl or 4-pyridyl, the 5-pyrimidine, 4-pyridazine or pyrazineradicals are especially suitable.

As cycloalkyl, cycloalkenyl or aryl radical lc, the cyclohexyl,cyclohex-1-enyl, cyclohex-2-enyl-, cyclohex-3-enyl-, as well as thephenyl radical are to be especially emphasized.

Alkenyl radical Id preferably is to exhibit up to 3 double bonds.

As halogen substituents that are possible in the heteroaryl radical ofFormula Ia, a chlorine or bromine atom are especially to be named.

If the heteroaryl radical of Formula Ia is alkyl substituted, thenmonosubstitution is preferred.

Cycloalkyl, cycloalkenyl or aryl radical Ic can be substituted by one ortwo chlorine and/or bromine atom(s). The radicals named can also besubstituted by one or two, optionally protected hydroxy and/or alkoxyradicals with 1 to 8 carbon atoms.

The compounds of general Formula I have a strong affinity for thegestagen receptor, without themselves developing gestagen activity. Theyare competitive antagonists of the progesterone (antigestagens); sincethey displace from the receptor the progesterone necessary formaintaining pregnancy, they are suitable for triggering abortions andfor inducing birth.

In addition to the named indications, the compounds according to theinvention can also be used for treatment of endometriosis, dysmenorrheaand hormone-associated tumors, such as e.g., breast cancer anddurosarcoma.

To characterize the antigestagen effect of the compounds according tothe invention, the abortive effectiveness was determined. The tests wereperformed on female rats with a weight of about 200 g. After successfulmating, the start of pregnancy was checked by detection of sperm invaginal smears. The day of the sperm detection counts at day 1 ofpregnancy (=d 1 p.c.).

The treatment of the animals with the substance to be tested in eachcase or with the solvent was performed on d. 5 to d. 7 p.c.

On d. 9 p.c., the animals were killed and the uteri were examined fornidations and absorptive points. The lack of nidations was considered anabortion.

As antigestagens there were studied:

A:17alpha-(3-hydroxyprop-1-(Z)-enyl)-17beta-hydroxy-11beta-(4-vinylphenyl)-4,9-estradien-3-one

B:17alpha-(prop-1-inyl)-17beta-hydroxy-11beta-(4-vinylphenyl)-4,9-estradien-3-one

C:17beta-(3-hydroxypropyl)-17alpha-hydroxy-13alpha-methyl-11beta-(4-isopropenylphenyl)-4,9-gonadien-3-one

D:11beta-(4-ethylphenyl)-17-hydroxy-17beta-(3-hydroxypropyl)-13alpha-methyl-4,9-gonadien-3-one

E:17-hydroxy-17beta-(3-hydroxypropyl)-13alpha-methyl-11beta-(4-vinylphenyl)-4,9-gonadien-3-one

F:17-hydroxy-17alpha-(3-hydroxyprop-(Z)-1-enyl)-11beta-[4-(3-pyridyl)-phenyl]-4,9-estradien-3-one

G:17-hydroxy-17beta-(3-hydroxypropyl)-13alpha-methyl-11beta-[4-(3-pyridyl)-phenyl]-4,9-gonadien-3-one

H:17-hydroxy-17beta-(3-hydroxypropyl)-13alpha-methyl-11beta-[4-(2-thiazolyl)-phenyl]-4,9-gonadien-3-one

I:17-hydroxy-17alpha-(3-hydroxy-(Z)-1-enyl)-11beta-[4-(3-thienyl)-phenyl]-4,9-estradien-3-one

K:17-hydroxy-17beta-(3-hydroxypropyl)-13alpha-methyl-11beta-[4-(3-furyl)-phenyl]-4,9-gonadien-3-one

L:17-hydroxy-17beta-(3-hydroxypropyl)-13alpha-methyl-11beta-[4-(3-thienyl)-phenyl]-4,9-gonadien-3-one

M:17-hydroxy-17alpha-(3-hydroxyprop-(Z)-1-enyl)-11beta-[4-(3-furyl)-phenyl]-4,9-estradien-3-one

N:17-hydroxy-17beta-3-hydroxypropyl)-13alpha-methyl-11beta-[4-(4-cyanophenyl)-phenyl]-4,9-gonadien-3-one

17-hydroxy-17beta-(3-hydroxypropyl)-13alpha-methyl-11beta-[4-(5-pyrimidyl)-phenyl]-4,9-gonadien-3-one

P:17-hydroxy-17alpha-(3-hydroxyprop-(Z)-1-enyl)-11beta-[4-(2-thiazolyl)-phenyl]-4,9-estradien-3-one

Q:11beta-[4-(dimethylamino)phenyl]-17beta-hydroxy-17alpha-(propion-1-yl)4,9(10)-estradien-3-one, RU-486 (EP-A 0057115).

The test substances were dissolved in a benzyl benzoate castor oilmixture (1:4 ratio). The treatment was performed subcutaneously (s.c.).

The results are presented in Table 1.

                  TABLE 1                                                         ______________________________________                                        Abortive effect of compounds (A) to (P) according to the                      invention in an early phase of pregnancy of rats. Treatment                   between d.5 p.c. and d.7 p.c., autopsy on d.9 p.c.                                                       Abortion rate                                                                 n abortions/                                       Compound  Dose (mg/animal/day s.c.)                                                                      n/total                                            ______________________________________                                        A         3.0              4/4                                                          1.0              4/4                                                          0.3              2/4                                                B         3.0              4/4                                                          1.0              3/4                                                          0.3              0/4                                                C         3.0              4/4                                                          1.0              0/4                                                D         3.0              3/4                                                          1.0              0/4                                                E         3.0              3/4                                                          1.0              0/4                                                F         3.0              4/4                                                          1.0              4/4                                                          0.3              0/4                                                G         3.0              4/4                                                          1.0              4/4                                                          0.3              4/4                                                          0.1              0/4                                                H         3.0              4/4                                                          1.0              3/4                                                          0.3              0/4                                                I         3.0              4/4                                                          1.0              4/4                                                          0.3              0/4                                                K         3.0              4/4                                                          1.0              4/4                                                          0.3              4/4                                                          0.1              0/4                                                L         3.0              4/4                                                          1.0              4/4                                                          0.3              0/4                                                M         3.0              4/4                                                          1.0              4/4                                                          0.3              4/4                                                          0.1              4/4                                                N         3.0              4/4                                                          1.0              4/4                                                          0.3              0/4                                                O         3.0              4/4                                                          1.0              4/4                                                          0.3              0/4                                                P         3.0              4/4                                                          1.0                                                                           0.3                                                                 Q         3.0              4/4                                                          1.0              2/4                                                          0.3              0/4                                                N         3.0              4/4                                                          1.0                                                                           0.3                                                                 O         3.0              4/4                                                          1.0                                                                           0.3                                                                 P         3.0              4/4                                                1.0                                                                           0.3                                                                           Sovent as control:                                                            0.2 ml of benzyl benzoate +                                                                          0/4                                                    castor oil (1:4)                                                              ______________________________________                                         If for R.sup.1 in the 13alphamethyl series stands a 3pyridyl residue (G)      or 3furyl residue (K) or in the 13betamethyl series a 3furyl residue (M),     the compounds according to the invention show very strong efficiency;         especially the substitution with a 3furyl residue in the 13betaseries is      to be emphasized: the tested compound M is even in a dose of 0.1              mg/animal/day still fully effective whereas compound Q which is to be         regarded as a standard compound is totally ineffective already in a dose      of 0.3 mg/animal/day.                                                    

To characterize the antiglucocorticoid effect, the influence of thesubstances according to the invention on tyrosineaminotransferase wasdetermined. The test system is based on a measurement of the activity ofthe liver enzyme tyrosine aminotransferase (TAT) in cultures of RHC (rathepatoma cells). The enzyme catalyzes the first step in themetabolization of tyrosine and can be induced in the liver as well as inhepatoma cells by glucocorticoids. The activity is easily measured incrude extracts (Granner and Tomkins, (1970) Meth. Enzymol. 15, 533). Theenzyme converts the amino group of tyrosine into 2-oxoglutaric acid. Indoing so, glutamic acid and p-hydroxyphenylpyruvate are produced. Inalkaline solution, from p-hydroxyphenylpyruvate there is formed the morestable p-hydroxybenzaldehyde, whose absorption is measured at 331 nm.The TAT activity in RHC cells shows a dose-dependent induction withcortisol (max. act. at 10⁻⁶ M) or dexamethasone (max. act. at 10⁻⁷ M).The activity can be stimulated above the basal value by a factor of 4-6.Simultaneous treatment with corticoid and antiglucocorticoid leads to areduction of the TAT activity.

Compounds A and E according to the invention show, in this test, about1%, compounds F and G about 2%, compound D about 5% and compound B about100% of the activity of11beta-[4-dimethylaminophenyl)-17beta-hydroxy-17alpha-(prop-1-inyl)-4,9-estradien-3-oneRU 486 [B], a substance that is to be considered standard (7th Int.Congress of Endocrinology Jul. 1-7, 1984, Quebec City, Canada: ExcerptsMedica, Amsterdam-Oxford-Princeton).

The compounds according to the invention of general formula I can beused in the form of pharmaceutical preparations. The production of thepreparations is performed according to galenic methods known in the artby mixing with organic or inorganic, inert carrier material that issuitable for enteral, percutaneous or parenteral administration.

The dosage of the compounds according to the invention for theindications given is between 1 and 1,000 mg daily.

The 13-alkyl-11beta-phenylgonanes of general formula I, in which the11beta-phenyl radical in 4 position carries the substituents accordingto the invention, are produced according to the process according toclaim 11.

In doing so, a compound of general formula II ##STR7## in which K meansa blocked keto group in the form of ketal, thioketal, oxime ormethyloxime, R¹ and R² have the above-mentioned meaning and R^(3') andR^(4') have the same meaning as R³ or R⁴, and hydroxy groups optionallypresent in R³ and hydroxy and/or acyl groups optionally present in R⁴are protected, with the effect of a dehydration agent that is capable ofreleasing the protected function(s), is subjected to water separationwith formation of 4(5) double bonds, is again protected in cycloalkyl,cycloalkenyl or aryl radical Id, alkylthio and/or dialkylamino radicalsoptionally present in radical Id are oxidized optionally to thecorresponding sulfoxide, Sulfone and/or N-oxide and then reactedoptionally with hydroxylamine hydrochloride in the presence of tertiaryamines at temperatures between -20° C. and +40° C.

The acidic treatment is performed in a way known in the art in that thecompound of Formula II, which contains at least two protective groups,is dissolved in a solvent miscible with water such as aqueous methanol,ethanol or acetone and catalytic amounts of mineral or sulfonic acidsuch as hydrochloric acid, sulfuric acid, phosphoric acid, perchloricacid or p-toluenesulfonic acid, or an organic acid, such as acetic acid,are left to act on the solution until water is separated and protectivegroups are removed. The reaction that occurs at temperatures of 0°-100°C., can also be performed with an acidic ion exchanger. The course ofthe reaction can be followed with analytical methods, for example bysamples taken by thin film chromatography.

To produce the compounds of general Formula II, there exist variouspossibilities according to the invention.

In one variant, starting from a compound of general Formula III ##STR8##the latter is reacted, according to the usual processes of the C₁₇ sidechain build-up by introduction of substituents R³ and R⁴ by nucleophilicaddition to the C₁₇ ketone and subsequent reactions ("Teipenoids andSteroids", Specialist Periodical Report, The Chemical Society, London,Vol. 1-12) into a compound of general Formula IV ##STR9##

Access to the 13alpha-methyl-or 13alpha-ethyl series (R₂ is in alphaposition) is performed--such described, e.g., in European patentapplication 0259 248--by irradiation of intermediate products of generalFormula III (Tetrahedron Letters 26., 2069 (1985), R₂ is in betaposition) with ultraviolet light.

While the nucleophilic addition to the 17-ketone of the 13beta-alkylseries yields only adducts with the hydroxy group in beta position andthe entering group in the alpha position to the five-membered ring, theaddition to the corresponding 13-epi-17-ketone occurs generally with theformation of both possible isomeric forms at C-17 which, however, areeasily separated by chromatography or fractionated crystallization. Inmany cases, both isomers are pharmacologically effective, even ifdifferences can exist in the strength of the effect.

The nucleophilic addition of HC≡CX in which X means hydrogen, alkyl with1-4 C atoms or halogen, is performed with the aid of a compound ofgeneral formula MC≡CX, in which X has the meaning indicated above and Mrepresents an alkaline metal.

The metallo-organic compound can also be formed in situ and brought toreaction with the 17-ketone. Thus, for example there can be left toreact on the 17-ketone, in a suitable solvent, acetylene and an alkalinemetal, in particular potassium, sodium or lithium, in the presence of analcohol or in the presence of ammonia. The alkaline metal can also beused in the form of, for example, methyl or butyl lithium. As solvents,dialkylether, tetrahydrofuran, dioxan, benzene and toluene are suitablein particular.

To produce the 17-chloroethinyl compound, the metallo-organicchloroethinyl compound is formed in situ from 1,1-dichloroethylene andan ethereal alkaline metal solution, such as for example methyl or butyllithium solution and is reacted with the 17-ketone in solvents, such astetrahydrofuran or diethylether.

The 17-ethinyl-17-hydroxy compounds can be hydrated in alcoholicsolution with mercury salt catalysis into the 17-acetyl-17-hydroxycompounds (Chem. Ber. [Chemical Reports] 111, (1978), 3086-3093).

The introduction of 3-hydroxypropine, propene or propane into the 17position is performed by reaction of the 17-ketone with metallizedderivatives of propargyl alcohol, for example with1-lithium-3-tetrahydropyran-2'-yloxy-propine-1 into the17-(3-hydroxy-1-propinyl)-17-hydroxy compounds, which can then behydrogenated into the 17-(3-hydroxypropyl or3-hydroxypropenyl)-17-hydroxy compounds. The hydrogenation must beperformed under conditions that guarantee exclusively attack on the C--Ctriple bond, without saturating the optionally present tetrasubstituted9(10) double bond. This succeeds, for example, with hydrogenation atroom temperature and normal pressure in solvents such as methanol,ethanol, propanol, tetrahydrofuran (THF) or acetic ester with theaddition of noble metal catalysts such as platinum or palladium.

The introduction of the homologs hydroxyalkyne, hydroxyalkene andhydroxyalkane groups is performed in a suitable way with homologs ofpropargyl alcohol.

The compound with the Z configured double bond in the hydroxypropenylgroup is produced by hydrogenation of the acetylenic triple bond with adeactivated noble metal catalyst (J. Fried, J. A. Edwards: OrganicReactions in Steroid Chemistry, Van Nostrand Reinhold Company 1972, page134 and H. O. House: Modern Synthetic Reactions 1972, page 19). Asdeactivated noble metal catalysts, for example 10% palladium on bariumsulfate in the presence of an amine or 5% palladium on calcium carbonatewith the addition of lead(II) acetate are suitable. The hydrogenation isinterrupted after the absorption of an equivalent hydrogen.

The compound with the E-configured double bond in the hydroxypropenylgroup is produced by reduction of the acetylenic triple bond in a wayknown in the art. In the literature there are described a whole seriesof methods for converting alkynes into trans-olefins, for example thereduction with sodium in liquid ammonia (J. Am. Chem. Soc, 63 (1941)216), with sodium amide in liquid ammonia (J. Chem. Soc., 1955, 3558),with lithium in low molecular amines (J. Am. Chem. Soc. 77 (1955) 3378),with boranes (J. Am. Chem. Soc. 93 (1971) 3395) and 94 (1971 (6560),with diisobutylaluminum hydride and methyllithium (J. Am. Chem. Soc. 89(1967) 5085) and in particular with lithium aluminum hydride/alcoholate(J. Am. Chem. Soc. 89 (1967) 4245). Another possibility is the reductionof the triple bond with chromium(II)-sulfate in the presence of water ordimethylformamide in a slightly acidic environment (J. Am. Chem. Soc. 85(1964) 4358) as well as generally the reduction by the action oftransition metal compounds with alternation in the oxidation step.

If end products of Formula I are desired with R₃ /R₄ in the meaning of##STR10## then 17-(3-hydroxypropyl) compound is oxidized in a way knownin the art, for example with Jones reagent, manganese dioxide,pyridinium dichromate, pyridinium chlorochromate, chromic acid-pyridineor with the Fetizon reagent silver carbonate/celite (Compt. Rend. 257(1968) 900).

To introduce the grouping ##STR11## the 17 ketone is converted withtosylmethylisocyanide into the 17-nitrile compound, from the 17-nitrilecompound there is obtained, with methyllithium or methylmagnesiumbromide, the 17-acetyl compound which, after enolization withK-tert.-butylate in tetrahydrofuran and reaction with methyl iodide,yields the desired grouping in 17 position.

The formation of the 17-cyanomethyl side chain is performed in a wayknown in the art from the 17-ketone, for example by the 17-spiro epoxideand cleavage of the spiro epoxide with HCH according to Z. Chem. 15,(1978) 259-260.

The introduction of the 17-hydroxyacetyl side chain is also performedaccording to methods known in the art, for example according to themethods described in J. Org. Chem. 47, (1982), 2993-2995.

Free hydroxy groups in the 17 position can be esterified or etherifiedin a way known in the art.

The compounds of general formula IV are then reacted, by Grignardaddition of an aryl Grignard compound that already carries in the 4position the desired substituent R¹, into a compound of general FormulaII that is further processed in the way already indicated.

But according to the invention it is also possible to react a compoundof general formula IV with a compound of the type ##STR12## in which Wmeans MgX (X=Br, I) or preferably Li (S. H. Lee, R. N. Hanson and D. E.Seitz, Tetrahedron Letters 25, 1751 (1984) and m 1,2,3,4, preferably 1or 4, with generation of a compound of general formula V ##STR13## inwhich K, R², R³ and R⁴ have the meaning already indicated (K Torssell,J. Goldman, T. E. Petersen: Liebigs Ann. Chem. 1973, 231-240).

From such a compound, the compound of general formula II is obtained ina Pd (O) catalyzed reaction in the presence of an R¹ Br compound, inwhich R¹ is the substituent R¹ desired in the end product.

If a compound of general formula II is to be produced in whichsubstituent R² is exclusively in alpha position, one can proceed so thata compound of general formula IV (R² =alpha position) is brought toreaction with a Grignard adduct of formula ##STR14## and the reactionproduct of general formula VI ##STR15## in which K, R², R^(3') andR^(4') have the meaning indicated above is further reacted to introducethe R¹ substituent into the 4 position of the 11beta configured phenylring in the presence of catalytic amounts of Pd(O) with a tin organiccompound of general formula R¹ Sn(C_(m) H_(2m+1))₃ (J. K. Stille. Angew.Chem. [Applied Chemistry] 96 (1986) 504-519) into the correspondingcompound of general formula II ##STR16##

Instead of the variant just mentioned, it is also possible to react acompound of general formula VI, first palladium(O) catalyzed with ahexaalkyldistannane [C_(m) H_(2m+1))₃ Sn]₂ (m=1,2,3,4, preferably 1 or4) into a compound of general formula V and to further process thelatter--as already indicated--into a compound of general formula II (Y.Yamamoto, Y. Azuma, H. Mitoh, Communications, pages 564-565, 1986, T. J.Bailey, Tet. Let., 27, pages 4407-4410, 1986.

The intermediate products of general formulas III to VI occurringaccording to claim 12 during the course of possible synthesis routes tothe initial products of general formula II can all be isolated insubstance and also count as part of the object of this invention.

Common to all process variants described above is the fact that into theC17-keto compound of general Formula III there are first introduced, bynucleophilic addition, the precursors R^(3'), R^(4') of the R^(s) and R⁴substituents or these two substituents themselves, with formation of acompound of general Formula IV and that only afterwards is the11beta-phenyl radical with the corresponding substitution patternestablished in the 4 position.

In contrast to this, according to the invention the synthesis of thecompounds of general formula I-can also be started with a13beta-alkyl-5,10-epoxide of general Formula VII ##STR17## in which Kand R² have the meaning indicated further above, in that into the latterthere is first introduced a phenyl radical that exhibits, in the 4position, the labile tin trialkyl group (alkyl, C₁ -C₄), preferably C₁or C₄) by Grignard addition of a suitable 4-(trialkylstannyl)-arylGrignard compound or alkylation with a 4-(trialkylstannyl)-aryllithiumcompound with formation of a compound of general formula VIII From acompound of general formula VIII, by coupling, which is transitionmetal-catalyzed, preferably Pd(O)-catalyzed, with a compound R¹ -Y(Y-Br,I) there is reached a compound of general formula IX ##STR18## next byoxidation of the 17beta-OH function and optionally subsequentirradiation with ultraviolet light (conversion of the beta-alkyl into a13alpha alkyl group) there is reached a compound of general formula X##STR19## in which the substituents have the meanings already indicatedand R² can be in alpha as well as beta position, into which then the R³and R⁴ substituents are introduced in the way already described bynucleophilic addition and they are separated from the protective groupspresent by acidic treatment with the release of a compound according tothe invention of general formula I.

The sequence of the reaction steps described here, running through thecompounds of formulas IX and X, starting from a compound of formula VIIIcan, starting from the same compound VIII, also be switched, in thatfirst the 17beta-OH is oxidized into the corresponding 17-keto function,next optionally it is irradiated with ultraviolet light and then, bytransition metal-catalyzed, preferably Pd(O)-catalyzed coupling with acompound R¹ -Y (Y=Br, I), the intermediate compound already describedabove of general formula X is generated, which is then reacted--also asalready described--into a compound of formula I. In doing so, a compoundof general formula XI is passed through ##STR20##

In a compound of general formula (XI) nucleophilic addition can also befirst performed to the C-17 atom to establish the radicals R³ and R⁴ ortheir precursors R^(3') and R^(4') with formation of a compound ofgeneral formula V which then, as already indicated, is further to beprocessed.

The compounds of general formulas VIII to XI, just as those of formulasIII to VI, can also be isolated in substance and belong to the object ofthis invention.

The following representative examples serve to explain the invention.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever.

In the foregoing and in the following examples, all temperatures are setforth uncorrected in degrees Celsius and, unless otherwise indicated,all parts and percentages are by weight.

The entire texts of all applications, patents and publications, if any,cited above and below, and of corresponding application P 38 22 770.3filed July 1, 1988 in the Federal Republic of Germany, are herebyincorporated by reference.

General Directions for Producing the Compounds of General Formula I byAcidic Splitting of the Compounds of General Formula II (Table 2)

A solution of x g of asteroid of general formula II in y ml of 70%acetic acid is stirred for z minutes at t° C. Next, the reaction mixtureis poured on ice water, neutralized by adding aqueous ammonia solutionand extracted with dichloromethane. The combined organic phases arewashed with a saturated common salt solution, dried over sodium sulfateand concentrated by evaporation in a vacuum. By chromatography on silicagel with a mixture of ethyl acetate/hexane, a g of the desired compoundof general formula I is obtained from the raw product.

General Directions for Production of the Compounds of General Formula II

A) by Grignard addition (Table 3)

10.6 mmol of magnesium chips is first placed under protective gas in 5ml of absolute tetrahydrofuran and mixed with 0.8 mmol of dibromoethane.After completed reaction, a solution of 10 mmol of haloaromate is slowlyinstilled in 11 ml of absolute tetrahydrofuran. After complete reaction,the Grignard solution is cooled to 0° C. and mixed with 0.28 mg ofcopper-(I)-chloride. Next a solution of 12 mmol of epoxide EP isinstilled in 7.5 ml of absolute tetrahydrofuran. The reaction mixture iswarmed slowly overnight to room temperature and then poured oversaturated ammonium chloride solution. The aqueous phase is extractedwith ethyl acetate, the organic phases are combined, washed withsaturated common salt solution and dried over sodium sulfate. Afterconcentration by evaporation in a vacuum, the residue is chromatographedon aluminum oxide (Merck, Step III, neutral) with a mixture of ethylacetate/hexane. Finally, y mmol of the desired adduct Y is isolated as awhite foam.

B) by coupling steroid stannanes of general formula V with arylbromides(Table 4)

2.27 mmol of stannyl steroid is placed in 60 ml of absolute dioxaneunder protective gas, mixed consecutively with 27.1 mmol of arylbromideas well as 0,228 mmol of bis-(triphenylphosphine)-palladium(II)-chlorideand refluxed 24 hours. The reaction mixture is filtered over belite,rewashed with ethyl acetate and mixed with the same volume of a 10%ammonia solution. After 30 minutes of stirring, the organic phase isseparated, washed with saturated NaCl solution and dried. Afterconcentration by evaporation in a vacuum, the residue is chromatographedon aluminum oxide (Merck, Step III, neutral) with a mixture of ethylacetate/hexane. A g of the desired compound of general formula II isobtained (Table 4).

C) by coupling bromosteroids of general Formula VI with heteroarylstannanes (preparation analogous to Lit. Ue. Organometal. Chem.,246(1983)163). [Table 5]

2.23 mmol of bromosteroid is placed in 50 ml of absolute dioxane, mixedconsecutively with 22.3 mmol of arylstannane as well as 0.228 mmol ofbis-(triphenylphosphine)-palladium(II)chloride and refluxed for 2 hours.After the working up described under a), b g of the desired compound ofgeneral formula II is obtained (Table 5).

EXAMPLE 117-(prop-1-inyl)-17beta-hydroxy-11beta-(4-vinylphenyl)-4,9-estradien-3-one(Table 2)

a) Production of the starting substrate for the Grignard addition17-(prop-1-inyl)-5alpha,10alpha-epoxy-3,3-(2,2-dimethyltrimethylenedioxy)-9(11)-estrene-17beta-ol

1.3 l of absolute tetrahydrofuran is saturated at 0° C. by introducingpropine with this gas. Next the solution is cooled down to -10° C. andmixed slowly with 166 ml of a 1.6 m solution of n-butyllithium inhexane. After 15 minutes of restirring at 0° C., a solution of 8.9 g of5alpha,10alpha-epoxy-3,3-(2,2-dimethyltrimethylenedioxy)-9(11)-estren-17-one isinstilled in 250 ml of absolute tetrahydrofuran. After the addition, thereaction mixture is stirred for another 30 minutes at 0° C. and thenpoured over ice water. The aqueous phase is extracted with ethylacetate, the organic phase is combined and washed with saturated commonsalt solution. After drying over sodium sulfate and concentration byevaporation in a vacuum, the residue obtained this way ischromatographed on aluminum oxide (Merck, step III, neutral) With amixture of ethyl acetate/hexane. 10.2 g of 17-(prop-1-inyl)-5alpha,10alpha-epoxy-3,3-(2,2-dimethyltrimethylenedioxy)-9(11)-estrene-17beta-olis isolated as white foam.

IR (KBr): 2245 cm⁻¹ C--C triple bond.

b)17-(prop-1-inyl)-11beta-(4-vinylphenyl-3,3-(2,2-dimethyltrimethylenedioxy)-9-estrene-5alpha,17beta-diol(Table 3)

EXAMPLE 217-(3-hydroxyprop-1-(Z)-enyl)-17beta-hydroxy-11beta-(4-vinylphenyl)-4,9-estradien-3-one

a) production of the starting substrate for the Grignard addition

17-[3-(tetrahydropyran-2-yloxy)-prop-1-(Z)-enyl]-5alpha,10alpha-epoxy-3,3-(2,2-dimethyltrimethylenedioxy-9(11)-estrene-17beta-ol

20 g of17-[3-(tetrahydropyran-2-yloxy)-prop-1-inyl]-5alpha,10alpha-epoxy-3,3-(2,2-dimethyltrimethylenedioxy-9(11)-estrene-17beta-olis dissolved in 400 ml of ethanol and mixed with 40 ml of pyridine and 4g of palladium/barium sulfate (10%). Next, hydrogenation is performed atnormal pressure with hydrogen. After taking up an equivalent hydrogen,the catalyst is separated by filtration over celite, the filtrate isconcentrated by evaporation and the residue is chromatographed onaluminum oxide (Merck, step II, neutral) with a mixture of ethylacetate/hexane. 18.8 g of17-[3-(tetrahydropyran-2-yloxy)-prop-1-(Z)-enyl]-5alpha,10alpha-epoxy-3,3-(2,2-dimethyltrimethylenedioxy)-9(11)-estrene-17beta-olis isolated as white foam.

b)17-[3-(tetrahydropyran-2-yloxy)-prop-1-(Z)-enyl]-11beta-(4-vinylphenyl)-3,3-(2,2-dimethyltrimethylenedioxy)-9-estren-5alpha,17beta-diolTable 3)

EXAMPLE 317-(3-hydroxypropyl)-17alpha-hydroxy-13alpha-methyl-11beta-(4-isopropenylphenyl)-4,3-gonadien-3-one

a) production of the substrate for the Grignard addition

17-[3-(tetrahydropyran-2-yloxy)-propyl]-13alpha-methyl-

5alpha,10alpha-epoxy-3,3-(2,2-dimethyltrimethylenedioxy)-9(11)-gonene-17alpha-ol

5.1 g of17-[3-(tetrahydropyran-2-yloxy)-prop-1-inyl]-13alpha-methyl-5alpha,10alpha-epoxy-3,3-[2,2-dimethyltrimethylenedioxy)-9,11-gonene-17alpha-olis dissolved in 150 ml of tetrahydrofuran and mixed with 2.55 g oftris-(triphenylphosphine)-rhodium-(1)-chloride. Next it is hydrogenatedwith hydrogen at normal pressure for 20 hours. Next the reaction mixtureis concentrated by evaporation and the residue is chromatographed onaluminum oxide (Merck, step. III, neutral) with a mixture of ethylacetate/hexane. 4.9 g of the desired compound is isolated as white foam.

b)17-[3-(tetrahydropyran-1-yloxy)-propyl]-13alpha-methyl-11beta-(4-isopropenylphenyl)-3,3-(2,2-dimethyltrimethylenedioxy)-9-gonene-5alpha,17alpha-diol(Table 3)

EXAMPLE 417-(3-hydroxypropyl)-17alpha-hydroxy-13alpha-methyl-11beta-(4-ethylphenyl)-4,9-gonadien-3-one

a) The substrate described in example 3a is used as starting product forthe Grignard addition.

b)17-[3-(tetrahydropyran-1-yloxy)-propyl]-13alpha-methyl-11beta-(4-ethylphenyl)-3,3-(2,2-dimethyltrimethylenedioxy)-9-gonene-5alpha,17alpha-diol(Table3)

EXAMPLE 517-(3-hydroxypropyl)-17alpha-hydroxy-13alpha-methyl-11beta-(4-vinylphenyl)-4,9-gonadien-3-one

a) The substrate described in example 3a is also used as the startingproduct for the Grignard addition.

b)17-[3-(tetrahydropyran-2-yloxy)-propyl]-13alpha-methyl-11beta-(4-vinylphenyl)-3,3-(2,2-dimethyltrimethylenedioxy)-9-gonene-5alpha,17alpha-diol(Table3)

EXAMPLE 6 (see example 8)17-hydroxy-17-(3-hydroxy-(Z)-prop-1-enyl)-11beta-(4-(3-thienyl)-phenyl)-4,9-estradien-3-one(Table 2)

a) The substrate described in example 2a is used as the starting productfor the Grignard addition with 1-chloro-4-(3-thienyl)-benzene(preparationanalogous to lit: Tetrahedron Letters 27, 4407 (1986).

b)3,3-(2,2-dimethyltrimethylenedioxy)-17-(3-tetrahydropyran-2-yloxy)-prop-(Z)-1-enyl]-11beta-[4-(3-thienyl)-phenyl]-estr-9-ene-5alpha,17beta-diol(Table 3)

EXAMPLE 717-hydroxy-17-(3-hydroxyprop-(Z)-1-enyl)-11beta-(4-(3-pyridyl)-phenyl)-4,9-estradien-3-one(Table 2)

a)3,3-(2,2-dimethyltrimethylenedioxy)-17-[3-(tetrahydropyran-2-yloxy)-prop-(Z)-1-enyl)-11beta-(4-tri-n-butylstannylphenyl)-estr-9-ene-5alpha,17beta-diol

30.6 mg of 1,4-bis-tri-n-butyl tin benzene (preparation analogous tolit: Chem. Ber. [Chemical Reports] 87,1255(1954) is placed underprotective gasin 120 ml of absolute tetrahydrofuran at -78° C. and mixeddrop by drop with 29 ml of a 1.6M solution of n-butyllithium in hexane.It is restirred for 2 hours at -78° C. and mixed with 2.0 g ofcopper(I)cyanide. After 30 minutes, a solution of 4.0 g of the compounddescribed in example 2 is instilled in 10 ml of absolutetetrahydrofuran. After the addition, the mixture is warmed to roomtemperature, restirred for 48 hours and then poured over ice water.

The aqueous phase is extracted with ethyl acetate, the organic phasesare combined and washed with saturated common salt solution. Afterdrying oversodium sulfate and concentration by evaporation in a vacuum,the residue obtained this way is chromatographed on silica gel with amixture of ethylacetate/hexane/triethylamine. 3.5 g of the compoundabove is obtained.

¹ H-NMR(CDCl₃ +d₅ -pyridene) δ=0.50 (s,3H, 18-H).0.86(s,3H,acetal-Mo),0.88, 0.90, 0.92(3t,9H,Me), 1.05(s, 3H,acetal-Mo),3.40-3.59(m, 4H,acetal-CH2), 4.26(d,J=7Hz,1H,11alpha,4.75(m,1H,H-THP-ether), 5.52-5.82(m,2H,H-olefin..C-20 andC-21), 7.15,7.30 (AA'BB'-system,J=9 Hz,4H,Ar-H).

b)3,3-(2,2-dimethyltrimethylenedioxy)-11beta-[4-(3-pyridyl)-phenyl]-17-[3'-(tetrahydropyran-2-yloxy)-prop-(Z)-1-enyl]-estr-9-ene-5alpha,17beta-diol (Table 4)

EXAMPLE 8 (see example 6)17-hydroxy-17alpha-(3-hydroxy-(Z)-prop-1-enyl)-11beta-[4-(3-thienyl)-phenyl]-4,9-estradien-3-one(Table 2)

a) The substrate described in example 7a is used as the starting productfor the coupling according to general directions B).

b)3,3-(2,2-dimethyltrimethylenedioxy)-17-[3-(tetrahydropyran-2-yloxy)-prop-(Z)-1-enyl]-11beta-[4-(3-thienyl)-phenyl]-estr-9-ene-5alpha,17beta-diol (Table 4)

The compound from example 6 is identical to the one from example 8.

EXAMPLE 9 17-hydroxy-17alpha(3-hydroxy-(Z)-prop-1-enyl]-11beta-[4-(3-furyl)-phenyl]-4,9-estradien-3-one(Table 2)

a) The substrate described in example 7a is used as the starting productfor the coupling according to general directions B.

b)3,3-(2,2-dimethyltrimethylenedioxy)-17-[3-(tetrahydropyran-2-yloxy)-prop-(Z)-1-enyl]-11beta-[4-(3-furyl)-phenyl]-estr-9-ene-5alpha,17beta-diol(Table4)

EXAMPLE 1017-hydroxy-17alpha(3-hydroxyprop-(Z)-1-enyl]-11beta-[4-(3-thiazolyl)-phenyl]-4,9-estradien-3-one(Table 2)

a) The substrate described in example 7a is used as the starting productfor the coupling according to general directions B.

b)3,3-(2,2-dimethyltrimethylenedioxy)-17-[3-(tetrahydropyran-2-yloxy)-prop-(Z)-1-enyl]-11beta-[4-(2-thiazolyl)-phenyl]-estr-9-ene-5alpha,17beta-diol(Table 4)

EXAMPLE 1117-hydroxy-17beta-(3-hydroxypropyl)-13alpha-methyl-11beta-[4-(3-pyridyl)-phenyl-1-4,9-gonadien-3-one(Table 2)

a)11beta-(4-bromophenyl)-3,3-(2,2-dimethyltrimethylenedioxy)-13alpha-methyl-17-[3-(tetrahydropyran-2-yloxy)-propyl]-9-gonene-5alpha,17alpha-diol

3.16 g of magnesium chips are placed under protective gas in 15 ml ofabsolute tetrahydrofuran and mixed with 0.1 ml of dibromoethane. Aftercompleted reaction, a solution of 30.7 g of 1,4-dibromobenzene in 500 mlof absolute tetrahydrofuran is instilled slowly. After complete reaction(30 minutes at 40° C., the Grignard solution is cooled to 0°C. and mixedwith 160 mg of copper-I-chloride. Next, a solution of 5.6 g oftheepoxide in 110 ml of absolute tetrahydrofuran described in example 3a isinstilled. The reaction mixture is worked up as described in the generaldirections. After column chromatography, 6.6 g of the above compound wasobtained.

b)3,3-(2,2-dimethyltrimethylenedioxy)-13alpha-methyl-17-[3-(tetrahydropyran-2-yloxy)-propyl]-11beta-(4-tri-n-butylstannylphenyl)-9-gonene-5alpha,17alpha-diol

6.27 g of the compound produced under a) is placed under protective gasin 180 ml of absolute dioxane, mixed with 15 ml of hexabutylditin, 625mg of bis-(triphenylphosphine)-palladium-II-chloride and 2.5 g oftetrabutylammonium chloride and then refluxed for 2 hours. Afterfiltration over celite, concentration by evaporation in a vacuum isperformed and the residue is chromatographed on aluminum oxide with amixture of ethyl acetate/hexane. 4.8 g of the above compound isobtained.

c)3,3-(2,2-dimethyltrimethylenedioxy-13alpha-methyl-11beta-[4-(3-pyridyl)-phenyl]-17-[3-tetrahydropyran-2-yloxy)-propyl]-9-gonene-5alpha,17alpha-diol(Table 4)

EXAMPLE 1217-hydroxy-17beta-(3-hydroxypropyl)-13alpha-methyl-11beta-[4-(4-cyanophenyl)-phenyl]-4,9-gonadien-3-one(Table 2)

a) The substrate described in example 11b is used as the startingproduct for the coupling according to general directions B.

b)3,3-(2,2-dimethyltrimethylenedioxy)-13alpha-methyl-11beta-[4-(4-cyanophenyl)-phenyl]-17-[3-(tetrahydropyran-2-yloxy)-propyl]-9-gonene-5alpha,17alpha-diol(Table 4)

EXAMPLE 1317-hydroxy-17beta-(3-hydroxypropyl)-13alpha-methyl-11beta-[4-(5-pyrimidyl)-phenyl]-4,9-gonadien-3-one(Table 2)

a) The substrate described in example 11b is used as the startingproduct for the coupling according to general directions B.

b)3,3-(2,2-dimethyltrimethylenedioxy)-13alpha-methyl-11beta-[4-(5-pyrimidyl)-phenyl]-17-[3-(tetrahydropyran-2-yloxy)-propyl]-9-gonene-5alpha,17alpha-diol (Table 4)

EXAMPLE 14 (see example 17)17-hydroxy-17beta-(3-hydroxypropyl)-13alpha-methyl-11beta-[4-(3-thienyl)-phenyl]-4,9-gonadien-3-one(Table 2)

a) The substrate described in example 11a is used for the startingproduct for the coupling according to general directions

b)3,3-(2,2-dimethyltrimethylenedioxy)-13alpha-methyl-17-[3-(tetrahydropyran-2-yloxy)-propyl]-11beta-[4-(3-thienyl)-phenyl]-9-gonene-5alpha,17alpha-diol (Table 5)

EXAMPLE 1517-hydroxy-17beta-(3-hydroxypropyl)-13alpha-methyl-11beta-[4-(3-furyl)-phenyl]-4,9-gonadien-3-one(Table 2)

a) The substrate described in example 11a is used as the startingproduct for the coupling according to general directions C.

b)3,3-(2,2-dimethyltrimethylenedioxy)-13alpha-methyl-11beta-[4-(3-furyl)-phenyl]-17-[3-(tetrahydropyran-2-yloxy)-propyl]-9-gonene-5alpha,17alpha-diol (Table 5)

EXAMPLE 1617-hydroxy-17alpha-(3-hydroxypropyl)-13alpha-methyl-11beta-[4-(2-thiazolyl)-phenyl]-4,9-gonadien-one(Table 2)

a) The substrate described in example 11a is used as the startingproduct for the coupling according to general directions C.

b)3,3-(2,2-dimethyltrimethylenedioxy)-13alpha-methyl-11beta-[4-(2-thiazolyl)-phenyl]-17-[3-(tetrahydropyran-2-yloxy)-propyl]-9-gonene-5alpha,17alpha-diol (Table 5).

EXAMPLE 17 (see example 14)17-hydroxy-17beta-(3-hydroxypropyl)-13alpha-methyl-11beta-[4-(3-thienyl)-phenyl]-4,9-gonadien-3-one(Table 2).

The compound of example 14 is identical to the one from example 17.

a)3,3-(2,2-dimethyltrimethylenedioxy)-11beta-(4-tri-n-butylstannylphenyl)-estr-9-ene-5alpha,17beta-diol.

From 10 g of3,3-(2,2-dimethyltrimethylenedioxy)-5alpha,10alpha-epoxy-estr-9(11)-en-17beta-olthere is obtained, as described under example 7a, 5.1 g of theabovecompound.

1-H-NMR(CDCl3+Pyd5) δ=0.38 (s,3H,1S-H), 0.87(s,3H,acetal-Me),0.89,0.91,0.93(3t,9H,Me),1.05(s,3H,acetal-Me),3.42-3.67(m,5H,17-H and acetal-CH2), 4.22(d,J=7Hz,1H,11alpha-H),4.40(s. wide, 1H,OH), 7.17, 7.31(AA'BB' system, J=9Hz,4H, Ar-H).

b)3,3-(2,2-dimethyltrimethylenedioxy)-11beta-[4-(3-thienyl)-phenyl]-estr-9-ene-5alpha,17beta-diolFrom 5.1 g of the compound described under 17a, 2.8 gof the abovecompound were obtained according to general directions a.

c)3,3-(2,2-dimethyltrimethylenedioxy)-5alpha-hydroxy-11beta-[4-(3-thienyl)-phenyl]-estr-9-en-17-one.

From 2.8 g of the compound described under 17b, 1.6 g of aluminumtriisopropylate and 11.6 ml of cyclohexanone in 60 ml of absolutetoluene,after 3 hours of heating on the water separator according to theusual working up and purification by column chromatography, 2.05 g ofthe above compound is obtained.

d)3,3-(2,2-dimethyltrimethylenedioxy)-5alpha-hydroxy-13alpha-methyl-11beta-[4-(3-thienyl)-phenyl]-9-gonen-17-one

From 2.05 g of the compound described under 17c in 600 ml of absolutedioxane, after 10 minutes of irradiation at room temperature with amercury high pressure lamp (Philips HPK 125) and chromatographicpurification, 840 mg of the above compound is obtained.

e)3,3-(2,2-dimethyltrimethylenedioxy)-13alpha-methyl-17-[3-(tetrahydropyran-2-yloxy)-1-propinyl]-11beta-(4-(3-thienyl)-phenyl]-9-gonene-5alpha,17alpha-diol

From 840 mg of the compound described under 17d in 20 ml of absolutetetrahydrofuran, 4.52 g of 2-(propargyloxy)tetrahydropyran in 80 ml ofabsolute tetrahydrofuran and 19 ml of a 1.6M solution of n-butyllithiuminhexane, after chromatographic purification, 370 mg of the abovecompound isobtained.

f)3,3-(2,2-dimethyltrimethylenedioxy)-13alpha-methyl-17-[3-(tetrahydropyran-2-yloxy)-propyl]-11beta-[4-(3-thienyl)-phenyl]-9-gonene-5alpha,17alpha-diol

From 370 mg of the compound produced under 17e, as described underexample 3a, 310 mg of the above compound is obtained.

EXAMPLE 183,3-(2,2-dimethyltrimethylenedioxy)-13alpha-ethyl-5alpha-hydroxy-11beta-[4-(3-thienyl)-phenyl]-9-gonen-17-one

From 2.9 g of3,3-(2,2-dimethyltrimethylenedioxy)-5alpha-hydroxy-18-methyl-11beta-[4-(3-thienyl)-phenyl]-estr-9-en-17-one(preparation analogous to example 17) there is obtained, as describedunder 17d, after chromatographic purification, 970 mg of the abovecompound.

1H-NMR(CDC13+Py-d5) δ=0.84(s.3H,acetal-Me) , 0.88(t,3H, 18-Me),1.02(s,3H,acetal-Me),3.35-3.56(m,4H,acetal-CH2),3.80(m,1H,11alpha-H),4.42(s, wide, 1H,OH), 7.13, 7.50 (AA'BB'-system, J=9Hz,4H,Ar-H), 7.38-7.45(m,3H,Ar-H).

EXAMPLE 1917beta-hydroxy-18-methyl-17-(1-propinyl)-11beta-[4-(3-thienyl)-phenyl]-estra-4,9-dien-3-one(Table 2).

1H-NMR(CDC13) δ=0.31(t,J=7 Hz,3H,18-Me), 1.91(s,3H,C≡C-Me),4.45(d,J=7Hz,1H,11alpha-H), 5.78(s,1H,4-H), 7.21,7.50 (AA'BB' system, J=9 Hz,4H,Ar-H), 7.34-7.46(m,3H,Ar-H).

a) The starting material in example 18 is used as the starting productfor the propinylation.

b)3,3-(2,2-dimethyltrimethylenedioxy)-18-methyl-17-(1-propinyl)-11beta-[4-(3-thienyl)-phenyl]-estr-9-ene-5alpha,17beta-diol

From 1.91 g of3,3-(2,2-dimethyltrimethylenedioxy-5alpha-hydroxy-18-methyl-11beta-[4-(3-thienyl)-phenyl]-estr-9-en-17-onein 40 ml of absolute tetrahydrofuran, 180 ml of a tetrahydrofuransolution saturated with propine and 24 ml of a 1.6M solution ofbutyllithium in hexane, after chromatographic purification, 1.47 g ofthe compound above is obtained.

                  TABLE 2                                                         ______________________________________                                                       Reaktions-                                                     Ansatz         parameter   Ausbeute                                           Beispiel                                                                              x [g]  y [ml]  t [°C.]                                                                      z [min]                                                                             a [g]                                                                              [α ]D.sup.20                    ______________________________________                                         1      10     100     50    60    6.54 131 (CHCl.sub.3 ;                                                             c = 0.53)                             Steroid lb             Steroid Beispiel 1                                      2      15     150     50    60    6.25 218 (CHCl.sub.3 ;                                                             c = 0.505)                            Steroid 2b             Steroid Beispiel 2                                      3      5      50      50    180   1.73 388 (CHCl.sub.3 ;                                                             c = 0.515)                            Steroid 3b             Steroid Beispiel 3                                      4      1.4    35      50    60    0.68 349 (CHCl.sub.3 ;                                                             c = 0.510)                            Steroid 4a             Steroid Beispiel 4                                      5      1.1    20      50    60    0.41 418 (CHCl.sub.3 ;                                                             c = 0.500)                            Steroid 5a             Steroid Beispiel 5                                      6      1.4    15      50    60    0.54 249 c = 0.52                          Steroid 6b             Steroid Beispiel 6                                      7      0.74   10      50    60    0.30 208 c = 0.505                         Steroid 7b             Steroid Beispiel 7                                      8      1.3    14      50    40    0.40 250 c = 0.52                          Steroid 8b             Steroid Beispiel 8                                      9      1.2    15      50    45    0.53 228 c = 0.505                         Steroid 9b             Steroid Beispiel 9                                     10      1.4    18      50    30    0.68 297 c = 0.505                         Steroid 10b            Steroid Beispiel 10                                    11      0.60    8      50    40    0.27  395 c = 0.51                         Steroid 11b            Steroid Beispiel 12                                    12      0.86   11      50    45    0.35 438 c = 0.51                          Steroid 12b            Steroid Beispiel 13                                    13      0.80   12      50    30    0.30 390 c = 0.51                          Steroid 13b            Steroid Beispiel 14                                    14      1.0    15      50    45    0.46 424 c = 0.505                         Steroid 14b            Steroid Beispiel 15                                    15      1.3    19      50    45    0.50 389 c = 0.51                          Steroid 15b            Steroid Beispiel 16                                    16      0.80    9      50    45    0.34 431 c = 0.5                           Steroid 16b            Steroid Beispiel 17                                    17      0.31    6      50    30    0.11 421 c = 0.51                          Steroid 17f            Steroid Beispiel 18                                    19      0.32    6      50    30    0.14 --                                    Steroid 19b            Steroid Beispiel 19                                    ______________________________________                                        Key:                                                                           [Beispiel] = example                                                          [Ansatz] = ingredients                                                        [Reaktionsparameter]= reaction parameters                                     [Ausbeute] = yield                                                       

                                      TABLE 3                                     __________________________________________________________________________    Ansatz                Halogenaromat  Ausbeute                                 Beispiel                                                                            Epoxid EP                                                                            [mmol]                                                                             [g] [X = Br, I]    Addukt Y                                                                             [mmol]                                                                             [g]                          __________________________________________________________________________    1     Steroid 1a                                                                           24   9.9                                                                                ##STR21##     Steroid 1b                                                                           20.3 10.5                         2     Steroid 2a                                                                           29.14                                                                              15                                                                                 ##STR22##     Steroid 2b                                                                           26.18                                                                              16.2                         3     Steroid 3a                                                                           14.52                                                                              7.5                                                                                ##STR23##     Steroid 3b                                                                           10.82                                                                              6.87                         4     Steroid 3a                                                                           2.75 1.42                                                                               ##STR24##     Steroid 4a                                                                           2.33 1.45                         5     Steroid 3a                                                                           2.03 1.05                                                                               ##STR25##     Steroid 5a                                                                           1.95 1.21                         6     Steroid 2a                                                                           5.13 3.0                                                                                ##STR26##     Steroid 6b                                                                           2.07 1.4                          __________________________________________________________________________    Key:                                                                           [Beispiel] = example                                                          [Ansatz] = ingredients                                                        [Epoxid] = epoxide                                                            [Halogenaromate] = haloaromate                                                [Ausbeute] = yield                                                            [Addukt] = adduct                                                        

                                      TABLE 4                                     __________________________________________________________________________    Ansatz              Halogenaromat                                                                             Ausbeute                                      Bsp.                                                                              Stannan X                                                                            [mmol]                                                                             [g] [X = Br, I] Addukt Y                                                                             [mmol]                                                                             [g]                               __________________________________________________________________________     7  Steroid 7a                                                                           2.36 2.08                                                                               ##STR27##  Steroid 7b                                                                           1.10 0.74                               8  Steroid 7a                                                                           2.27 2.00                                                                               ##STR28##  Steroid 8b                                                                           1.93 1.30                               9  Steroid 7a                                                                           2.31 2.04                                                                               ##STR29##  Steroid 9b                                                                           1.82 1.20                              10  Steroid 7a                                                                           2.51 2.21                                                                               ##STR30##  Steroid 10b                                                                          2.07 1.40                              11  Steroid 11b                                                                          1.84 1.63                                                                               ##STR31##  Steroid 11c                                                                          0.89 0.60                              12  Steroid 11b                                                                          2.26 2.00                                                                               ##STR32##  Steroid 12b                                                                          1.23 0.86                              13  Steroid 11b                                                                          3.31 2.93                                                                               ##STR33##  Steroid 13b                                                                          1.19 0.80                              __________________________________________________________________________    Key:                                                                           [Bsp.] = example                                                              [Ansatz] = ingredients                                                        [Stannan] = stannane                                                          [Halogenaromat] = haloaromate                                                 [Ausbeute] = yield                                                            [Addukt] = adduct                                                        

                                      TABLE 5                                     __________________________________________________________________________    Ansatz              Heteroarylstannan                                                                       Ausbeute                                        Bsp.                                                                              Halogen X                                                                            [mmol]                                                                             [g] (X = SnBu3)                                                                             Addukt Y                                                                             [mmol]                                                                             [g]                                 __________________________________________________________________________    14  Steroid 11a                                                                          2.22 1.50                                                                               ##STR34##                                                                              Steroid 14b                                                                          1.53 1.0                                 15  Steroid 11a                                                                          2.22 1.50                                                                               ##STR35##                                                                              Steroid 15b                                                                          1.97 1.3                                 16  Steroid 11a                                                                          1.48 1.00                                                                               ##STR36##                                                                              Steroid 16b                                                                          1.18 0.8                                 __________________________________________________________________________     [Bsp.] = example                                                              [Ansatz] = ingredients                                                        [Heteroarylstannan] = heteroarylstannane                                      [Ausbeute] = yield                                                            [Addukt] = adduct                                                        

The preceding examples can be repeated with similar success bysubstitutingthe generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertainthe essential characteristics of this invention, and, withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

We claim:
 1. 13-alkyl-11beta-phenyl-gonanes of formula I ##STR37## inwhich Z is an oxygen atom or the hydroxyimino grouping N--OH,R¹ isa)cycloalkyl radical, optionally substituted by one or more halogen,optionally protected hydroxy, alkoxy, cyano, oxidized alkylthio,optionally in the form of sulfoxide or sulfone and/or dialkylaminoradicals, optionally in the form of the N-oxide, b) a cycloalkenylradical, optionally substituted by one or more halogen, optionallyprotected hydroxy, alkoxy, cyano, oxidized alkylthio, optionally in theform of sulfoxide or sulfone and/or dialkylamino radicals, optionally inthe form of the N-oxide, c) an aryl radical, optionally substituted byone or more halogen, optionally protected hydroxy, alkoxy, cyano,oxidized alkylthio, optionally in the form of sulfoxide or sulfoneand/or dialkylamino radicals, optionally in the form of the N-oxide, ord) an alkenyl radical exhibiting straight-chain or branched, one or moredouble bonds with 2 to 10 carbon atoms, R² is an alpha- or beta-positionmethyl or ethyl radical, and if R² is in the alpha-position, R¹additionally stands for a straight-chain or branched alkyl radical with1 to 10 carbon atoms, and if R² is in the beta-position, R¹ additionallystands for an ethyl radical, but R¹ cannot be a dialkylamino substitutedaryl radical or the N-oxide of a dialkylamine substituted arylradical,where R² is in the alpha-position, R³ /R⁴ mean: ##STR38## whereR² is in the beta position, R³ /R⁴ mean: ##STR39## where R₅ is ahydrogen atom or an acyl radical with 1 to 4 carbon atoms, Y is ahydrogen, chlorine, fluorine, iodine or bromine atom, an alkyl,hydroxyalkyl, alkoxyalkyl or acyloxyalkyl group each with 1 to 4 carbonatoms in the alkyl or acyl radical, R₆ is a hydrogen atom, a hydroxylgroup, an alkyl, O-alkyl, or O-acyl group each with 1 to 4 carbon atoms,o is 0, 1, 2 or 3, R₇ is a hydroxy or cyanide radical, an O-alkyl orO-acyl group each with 1 to 4 carbon atoms and k is 0, 1 or
 2. 2.13-alkylgonanes according to claim 1, wherein R² is in the beta-positionand R¹ is selected from ethyl, vinyl and isopropyl and R⁴ is selectedfrom 17α-3-hydroxypropenyl and 17α-1-propinyl.
 3. 13-alkylgonanesaccording to claim 1, wherein R² is in the alpha-position and R¹ isselected from ethyl, vinyl, isopropenyl and 4, 3 or2-dimethylaminophenyl and either R³ or R⁴ is 17β-3-hydroxypropyl. 4.13-alkylgonanes according to claim 1, wherein cycloalkyl, cycloalkenylor aryl radical R¹ is the cyclohexyl, a cyclohexenyl or the phenylradical.
 5. 13-alkylgonanes according to claim 1, wherein alkenylradical R¹ exhibits up to 3 double bonds.
 6. 13-alkylgonanes accordingto claim 1, wherein cycloalkyl, cycloalkenyl or aryl radical R¹ issubstituted by one or two chlorine and/or bromine atom(s). 7.13-alkylgonanes according to claim 1, wherein the cycloalkyl,cycloalkenyl or aryl radical is substituted by one or two, optionallyprotected hydroxy and/or alkoxy radicals with 1 to 8 carbon atoms.
 8. Apharmaceutical antigestagenic preparation comprising a pharmaceuticallyacceptable carrier and a compound according to claim
 1. 9.11beta-(4-ethylphenyl)-17-hydroxy-17beta-(3-hydroxypropyl)-13alpha-methyl-4,9-gonadien-3-one;11beta-(4-ethylphenyl-17-hydroxy-17alpha-(3-hydroxypropyl)-13alpha-methyl-4,9-gonadien-3-one;17-hydroxy-17beta-(3-hydroxypropyl)-13alpha-methyl-11beta-(4-vinylphenyl)-4,9-gonadien-3-one;17-hydroxy-17alpha-(3-hydroxypropyl)-13alpha-methyl-11beta-(4-vinylphenyl)-4,9-gonadien-3-one;17-hydroxy-17beta-(3-hydroxypropyl)-11beta-(4-isopropenylphenyl)-13alpha-methyl-4,9-gonadien-3-one;17-hydroxy-17alpha-(3-hydroxypropyl)-11beta-(4-isopropenylphenyl-13alpha-methyl-4,9-gonadien-3-one;11beta-[4-(4-dimethylaminophenyl)-phenyl]-17-hydroxy-17beta-(3-hydroxypropyl)-13alpha-methyl-4,9-gonadien-3-one;11beta-[4-(3-dimethylaminophenyl)-phenyl]-17-hydroxy-17alpha-(3-hydroxypropyl)-13alpha-methyl-4,9-gonadien-3-one;11beta-[4-(3-dimethylaminophenyl)-phenyl]-17-hydroxy-17beta-(3-hydroxypropyl)-13alpha-methyl-4,9-gonadien-3-one;11beta-[4-(3-dimethylaminophenyl)-phenyl]-17-hydroxy-17alpha-(3-hydroxypropyl)-13alpha-methyl-4,9-gonadien-3-one;11beta-[4-(2-dimethylaminophenyl)-phenyl]-17-hydroxy-17beta-(3-hydroxypropyl)-13alpha-methyl-4,9-gonadien-3-one;11beta-[4-(2-dimethylaminophenyl)-phenyl]-17-hydroxy-17alpha-(3-hydroxypropyl)-13alpha-methyl-4,9-gonadien-3-one;17-hydroxy-17beta-(3-hydroxypropyl)-13alpha-methyl-11beta[4-(2-thiazolyl)-phenyl]-4,9-gonadien-3-one;11beta-(4-ethylphenyl)-17-hydroxy-17alpha-(3-hydroxyprop-(Z)-1-enyl)-4,9-estradien-3-one;17-hydroxy-17alpha-(3-hydroxyprop-(Z)-1-enyl)-11beta-(4-vinylphenyl)-4,9-estradien-3-one;17-hydroxy-17alpha-(3-hydroxyprop-(Z)-1-enyl)-11beta-(4-isopropenylphenyl)-4,9-estradien-3-one;17-hydroxy-17alpha-(3-hydroxyprop-(Z)-1-enyl)-11beta-[4-(2-thienyl)-phenyl]-4,9-estradien-3-one;11beta-(4-ethylphenyl)-17-hydroxy-17alpha-(1-propinyl)-4,9-estradien-3-one;or17-hydroxy-17alpha-(1-propinyl)-11beta-(4-vinylphenyl)-4,9-estradien-3-one.10. A pharmaceutical antigestagenic preparation comprising apharmaceutically acceptable carrier and a compound according to claim 9.